EP1430894A1 - Lymphocytic activation inhibitor and remedial agent for autoimmune disease - Google Patents

Lymphocytic activation inhibitor and remedial agent for autoimmune disease Download PDF

Info

Publication number
EP1430894A1
EP1430894A1 EP02798032A EP02798032A EP1430894A1 EP 1430894 A1 EP1430894 A1 EP 1430894A1 EP 02798032 A EP02798032 A EP 02798032A EP 02798032 A EP02798032 A EP 02798032A EP 1430894 A1 EP1430894 A1 EP 1430894A1
Authority
EP
European Patent Office
Prior art keywords
ring
substituted
compound
indol
chloro
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP02798032A
Other languages
German (de)
French (fr)
Other versions
EP1430894A4 (en
Inventor
Takahisa Hanada
Toshihiko Yamauchi
Kenichi Chiba
Takashi Owa
Takayuki Hida
Norimasa Miyamoto
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eisai R&D Management Co Ltd
Original Assignee
Eisai Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Eisai Co Ltd filed Critical Eisai Co Ltd
Publication of EP1430894A1 publication Critical patent/EP1430894A1/en
Publication of EP1430894A4 publication Critical patent/EP1430894A4/en
Withdrawn legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin

Definitions

  • the present invention relates to a lymphocyte activation inhibitor.
  • the present invention also relates to a therapeutic agent for an autoimmune disease, and more specifically to a therapeutic agent that is effective for rheumatism, multiple sclerosis, neuro-autoimmune diseases, type I (insulin-dependent) diabetes, systemic lupus erythematosus (SLE), inflammatory bowel diseases (IBD), and Sjogren's syndrome.
  • autoantigen-specific lymphocytes significantly contribute to aggravation of a pathological condition in autoimmune diseases.
  • the autoantigen-specific lymphocytes get activated and proliferate by recognizing a part of the self as a foreign body, and induce disorders in tissues by causing activation of cells in other immune systems, thereby playing a significantly important role in the development of pathological conditions. Therefore, inhibiting the lymphocyte activation induced by an antigen allows the inhibition of development of an autoimmune disease.
  • autoimmune disease examples include rheumatism, multiple sclerosis, neuro-autoimmune diseases (Guillain-Barre syndrome, neuro-Behcet's disease, etc.), type I (insulin-dependent) diabetes, systemic lupus erythematosus (SLE), inflammatory bowel diseases (IBD), and Sjogren's syndrome, which are known as intractable diseases [reference document: Clinical Immunology and Immunopathology, 84, 223-243 (1997)].
  • lymphocyte activation inhibitors based on various action mechanisms have been clinically used for treatments of the autoimmune diseases described above. However, it is known that they accompany severe side effects in some cases, though their effectiveness are recognized. As a result, they have not been used widely, and the development of a lymphocyte activation inhibitor having a lower toxicity has been desired.
  • JP 07-165708 A, JP 08-231505 A, and JP 2000-247949 A disclose a sulfonamide compound or a sulfonic acid ester compound, whereas those publications describe nothing about the lymphocyte activation inhibition effect thereof.
  • the inventors of the present invention have made intensive studies for seeking an excellent lymphocyte activation inhibitor, and found that a sulfonamide compound and a sulfonic acid ester compound having a bicyclic hetero ring have an excellent lymphocyte activation inhibition effect and also have less toxicity, thus completing the present invention.
  • the present invention also provides a therapeutic agent for an autoimmune disease, comprising, as an active ingredient, a sulfonamide derivative or sulfonic acid ester derivative represented by the above general formula (I), or a pharmacologically acceptable salt thereof, or a hydrate thereof.
  • W is a single bond. More preferably, X and Z are -NH-, and Y is a carbon atom.
  • the ring B is benzene or pyridine, each of which may be substituted.
  • the ring C is pyrrole which may be substituted.
  • the ring A is benzene or pyridine, each of which may be substituted; the ring B is benzene which may be substituted; the ring C is pyrrole which may be substituted; W is a single bond; and X and Z are -NH-.
  • autoimmune disease examples include cellular autoimmune diseases, rheumatism, multiple sclerosis, neuro-autoimmune diseases, type I (insulin-dependent) diabetes, systemic lupus erythematosus, inflammatory bowel diseases, and Sjogren's syndrome.
  • the agent further comprises a drug having a neuron-protecting effect.
  • the "monocyclic or bicyclic aromatic ring which may be substituted" represented by the ring A is an aromatic hydrocarbon ring or an aromatic heterocyclic ring containing at least one of nitrogen, oxygen and sulfur atoms, each of which may have one to three substituents thereon.
  • aromatic rings included in the ring A include pyrrole, pyrazole, imidazole, thiophene, furan, thiazole, oxazole, benzene, pyridine, pyrimidine, pyrazine, pyridazine, naphthalene, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, indole, isoindole, indolizine, indazole, benzofuran, benzothiophene, benzoxazole, benzimidazole, benzopyrazole, benzothiazole and so forth.
  • substituents may have one to three substituents. When two or more substituents are present, they may be the same or different.
  • substituents include an amino group which may be substituted with a lower alkyl gourp or a lower cycloalkyl group; a lower alkyl group; a lower alkoxy group; hydroxyl; nitro; mercapto; cyano; a lower alkylthio group; a halogen group; a group represented by the formula -a-b wherein a represents a single bond, -(CH 2 ) k -, -O-(CH 2 ) k -, -S-(CH 2 ) k - or -N(R 3 )-(CH 2 ) k -, k is an integer of 1 to 5, R 3 represents a hydrogen atom or a lower alkyl group, and b represents -CH 2 -d (wherein d represents an amino group which may be substituted with a lower alkyl
  • both of the alkyl groups may bond to form a 5- or 6-membered ring.
  • the ring A is a nitrogen-containing heterocyclic ring having hydroxyl or mercapto, these groups may present in the form of an oxo or thioxo group by resonance.
  • the "6-membered unsaturated hydrocarbon ring or 6-membered unsaturated heterocyclic ring containing one nitrogen atom as a heteroatom, which may be substituted" represented by the ring B means benzene or pyridine which may be partially hydrogenated. It may have one or two of substituents on the ring, and when two of substituents are present, they may be the same or different.
  • the "5-membered heterocyclic ring containing one or two nitrogen atoms, which may be substituted" represented by the ring C means pyrrole, pyrazole or imidazole which may be partially hydrogenated. It may have one or two of substituents on the ring, and when two of substituents are present, they may be the same or different.
  • Examples of the substituents that the rings of B and C may have include a halogen group, cyano, a lower alkyl group, a lower alkoxy group, hydroxyl, oxo, a group represented by the formula -C(O)-r (wherein r represents a hydrogen atom, an amino group which may be substituted with a lower alkyl group, a lower alkyl group, a lower alkoxy group or hydroxyl), an amino group substituted with a lower alkyl group, trifluoromethyl and so forth.
  • the lower alkyl group in the definitions of R 1 and R 2 as well as the substituents that the rings of A, B and C may have means a linear or branched alkyl group having 1 to 6 carbon atoms, and examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl (amyl), isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2,3-dimethyl
  • methyl,. ethyl, n-propyl, isopropyl, n-butyl and isobutyl are preferred, and methyl, ethyl, n-propyl and isopropyl are most preferred.
  • the lower cycloalkyl group mentioned in the definitions of the substituents that the ring of A may have means a cycloalkyl group having 3 to 8 carbon atoms, and examples thereof include cyclopropyl, cyclopentyl, cyclohexyl and so forth.
  • the lower alkoxy mentioned in the definitions of the substituents that the rings of A, B and C may have means an alkoxyl' group derived from the aforementioned lower alkyl group, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. Among these, methoxy and ethoxy are most preferred.
  • the lower alkylthio group means an alkylthio group derived from the aforementioned lower alkyl group.
  • examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and so forth.
  • the sulfonamide derivatives or the sulfonic acid ester derivatives represented by the general formula (I) may form a salt with an acid or a base.
  • the active ingredient used in the present invention also includes salts of the sulfonamide derivatives or the sulfonic acid ester represented by the general formula (I).
  • the salt with an acid include salts with inorganic acids, such as hydrochlorides, hydrobromides and sulfates, and salts with organic acids such as acetic acid, lactic acid, succinic acid, fumaric acid, maleic acid, citric acid, benzoic acid, methanesulfonic acid and p-toluenesulfonic acid.
  • Examples of the salt with a base include salts with inorganic bases, such as sodium salts, potassium salts and calcium salts and salts with organic bases such as triethylamine, arginine and lysine.
  • the compounds include hydrates and optical isomers of these compounds if they are present.
  • the sulfonamide derivative or the sulfonic acid ester derivative represented by the general formula (I), a pharmacologically acceptable salt thereof, or a hydrate of the same may be manufactured by various methods. Among them, representative methods are described in JP 07-165708 A, JP 08-231505 A, and JP 2000-247949 A.
  • the compound represented by the general formula (I) has an excellent lymphocyte activation inhibition effect.
  • the compound represented by the general formula (I) may be used as an active ingredient for a lymphocyte activation inhibitor. It may also be used as an active ingredient of a therapeutic agent for diseases in which inhibition of lymphocyte activation is effective to treatment thereof.
  • a method for inhibiting lymphocyte activation comprising administering an effective amount of the compound represented by the general formula (I); and a method for treating a disease in which inhibition of lymphocyte activation is effective to treatment thereof, comprising administering an effective amount of the compound represented by the general formula (I).
  • the present invention there is provided a use of the compound represented by the general formula (I) in manufacture of a lymphocyte activation inhibitor, and a use of the compound represented by the general formula (I) in manufacture of a therapeutic agent for a disease in which inhibition of lymphocyte activation is effective to treatment thereof.
  • the phrase "the compound represented by the general formula (I) as an active ingredient” includes a compound that generates the compound represented by the general formula (I) due to in vivo metabolism such as oxidation, reduction, and hydrolysis.
  • administering the compound represented by the general formula (I)” and “use of the compound represented by the general formula (I)” in the present invention also include administering and using a compound which generates the compound represented by the general formula (I) due to in vivo metabolism such as oxidation, reduction, and hydrolysis, respectively.
  • treatment also includes alleviating a symptom of a disease.
  • Examples of the disease in which inhibition of lymphocyte activation is effective to treatment thereof include autoimmune diseases.
  • Examples of the autoimmune diseases include rheumatism, multiple sclerosis, neuro-autoimmune diseases (Guillain-Barre syndrome, neuro-Behcet's disease, etc.), type I (insulin-dependent) diabetes, systemic lupus erythematosus (SLE), inflammatory bowel diseases (IBD), and Sjogren's syndrome, etc.
  • the compound represented by the general formula (I) may be used in a preparation made by a general method.
  • it may be a composition with a carrier (if used for a medicine, a pharmacologically acceptable carrier).
  • the dose is different depending on degree of a symptom, age of a patient, sex, body weight, sensibility difference, administration method, administration timing, administration interval, medicinal characteristics, preparation, allegation, type, type of active ingredient, or the like.
  • the dose is generally 10 to 6,000 mg, preferably about 50 to 4,000 mg, more preferably 100 to 3,000 mg per day for an adult, which was separately administered generally 1 to 3 time(s) in a day, but there is no particular limitation thereto.
  • a vehicle and optionally with a binder, disintegrator, lubricant, colorant, corrective, etc. are added to a base, and a mixture thereof is then treated in accordance with a conventional method to form tablets, coated tablets, granules, fine granules, powder, capsules, etc.
  • Examples of the vehicle include lactose, cornstarch, saccharose, glucose, sorbitol, crystalline cellulose, and silicon dioxide.
  • Examples of the binder include polyvinyl alcohol, ethylcellulose, methylcellulose, acacia gum, hydroxypropylcellulose, and hydroxypropylmethylcellulose.
  • Examples of the lubricant include magnesium stearate, talc, and silica.
  • As the colorant one permitted to add to a drug is used.
  • Examples of the corrective include cocoa powder, menthol, aromatic acid, peppermint oil, borneol, and cinnamon powder. As a matter of course, those tablets and granules may optionally be coated appropriately with sugar, gelatin, etc.
  • a pH regulator, a buffer, a suspending agent, a solubilizer, a stabilizer, an isotonizing agent, a preservative, etc. are optionally added to a base, and a mixture thereof is then treated in accordance with a conventional method to form an injection for intravenous, hypodermic, or intramuscular injection.
  • the injection may optionally be treated in accordance with a conventional method to form a freeze-dry product.
  • suspending agent examples include methylcellulose, polysorbate 80, hydroxyethylcellulose, acacia gum, tragacanth powder, sodium carboxymethylcellulose, and polyoxyethylenesorbitan monolaurate.
  • solubilizing agent examples include polyoxyethylene hardened castor oil, polysorbate 80, nicotinic acid amide, polyoxyethylenesorbitan monolaurate, macrogol, and castor oil fatty acid ethyl ester.
  • Examples of the stabilizer include sodium sulfite and sodium metasulfite.
  • Examples of the preservative include methyl paraoxybenzoate, ethyl paraoxybenzoate, sorbic acid, phenol, cresol, and chlorocresol.
  • the therapeutic agent for an autoimmune disease is preferred to further include a drug having a neuron-protecting effect.
  • the neuron-protecting effect means an effect of inhibiting a morbid change such as nerve axonal degeneration in multiple sclerosis by directly effecting to nerves.
  • Examples of the drug having a neuron-protecting effect include a glutamic acid antagonist, a sodium channel antagonist, a calcium channel antagonist, etc.
  • the compound represented by the general formula (I) and the drug having a neuron-protecting effect may be mixed or separately encased to be packed in a unit.
  • the compound represented by the general formula (I) and the drug having a neuron-protecting effect may be administered simultaneously or in order.
  • PLP proteolipid protein
  • the effect of a drug to the reaction was examined to evaluate the inhibition effect of the drug for lymphocyte activation.
  • a female SJL/J mouse was immunized with an adjuvant containing a PLP partial peptide (PLP 139-151 ) under ether anesthesia.
  • a DBA/1JN male mouse (7 weeks of age) was sensitized by intracutaneously injecting in the tail part thereof with 0.1 ml of an emulsion solution obtained by mixing a 0.3% bovine-derived type II collagen solution with the same amount of a Freund's complete adjuvant.
  • a booster was conducted in a similar way to cause arthritis.
  • the subjective compound was made into a solution (5 mg/ml) according to a general method, and the day of the booster and 3 days thereafter, the solution was intravenously administered in an amount of 10 ml/kg (50 mg/kg).
  • 8 mice were used for each of a control group and a drug-administered group.
  • the condition of arthritis was evaluated macroscopically on limbs and graded into 5 score levels (0; normal, 1; flare on a finger joint, 2; slight' edema on an entire leg, 3; edema on an entire leg, and 4; severe edema on an entire leg), to be shown as a total sum.
  • the compound had an obvious inhibition effect for the crisis and development of arthritis. The effect lasted even after the second administration and the inhibition effect was recognized even 36 days after the initial sensitization, i.e., 12 days after administration (Fig. 1).
  • the mouse collagen-induced arthritis model described above is a model in which a lymphocyte activated by reacting with an immunized collagen recognizes an autotissue, particularly collagen in a joint tissue and causes an immunoreaction to induce arthritis, and is widely recognized as a model for evaluating a pharmacological. effect of a compound having a lymphocyte activation inhibition effect (e.g., Br. J. Rheumatol., 33, 798 (1994)).
  • Pharmacological experimental example 3 Effect in an experimental encephalomyelitis model
  • a Freund's complete adjuvant (Difco, containing 0.6 mg/ml of M. tuberculosis H37Ra) containing the PLP peptide (p139-151, Toray Research Center) was subcutaneously injected to a female SJL/J mouse in the back thereof under ether anesthesia for immunization (initial sensitization).
  • immunization initial sensitization
  • immunization was conducted again with the antigen. Over several weeks thereafter, abnormalities in limbs, a tail, and righting reflexes were graded into scored levels and recorded.
  • the subjective compound was orally administered in an amount of 200 mg/kg from 5th day to 12th day after the initial sensitization.
  • 12 mice were used for each of a control group and a drug-administered group.
  • those compounds delayed expression of abnormality appeared in the mice, and alleviated the severity (Fig. 2).
  • the experimental encephalomyelitis model described above is a model in which a lymphocyte activated by reacting with an immunized PLP peptide causes an immunoreaction to induce encephalomyelitis, and is widely recognized as a model for evaluating a pharmacological effect of a compound having a lymphocyte activation inhibition effect (e.g., Agents and Actions, 27, 351-355 (1989); and Agents and Actions, 35, 79-84 (1992)).
  • the compound represented by the general formula (I) has an excellent lymphocyte activation inhibition effect. It is therefore considered to be useful as a therapeutic agent for autoimmune diseases, for treatment of rheumatism, multiple sclerosis, neuro-autoimmune diseases (Guillain-Barre syndrome, neuro-Behcet's disease, etc.), type I (insulin-dependent) diabetes, systemic lupus erythematosus (SLE), inflammatory bowel diseases (IBD), and Sjogren's syndrome, etc.
  • a lymphocyte activation inhibitor and a therapeutic agent for an autoimmune disease are provided.

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Diabetes (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Endocrinology (AREA)
  • Rheumatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Hospice & Palliative Care (AREA)
  • Ophthalmology & Optometry (AREA)
  • Psychiatry (AREA)
  • Emergency Medicine (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Pain & Pain Management (AREA)
  • Transplantation (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A lymphocyte activation inhibitor and a therapeutic agent for an autoimmune disease, each comprising, as an active ingredient, a sulfonamide derivative or sulfonic acid ester derivative represented by the following general formula (I):
Figure 80000001
wherein the ring A represents a monocyclic or bicyclic aromatic ring which may be substituted,
the ring B represents a 6-membered unsaturated hydrocarbon ring or a 6-membered unsaturated heterocyclic ring containing one nitrogen atom as a heteroatom, each of which may be substituted,
the ring C represents a 5-membered heterocyclic ring containing one or two nitrogen atoms, which may be substituted,
W represents a single bond or -CH=CH-,
X represents -N(R1)- or an oxygen atom,
Y represents a carbon atom or a nitrogen atom,
Z represents -N(R2)- or a nitrogen atom, and
R1 and R2 may be identical or different and each represents a hydrogen atom or a lower alkyl group, or a pharmacologically acceptable salt thereof, or a hydrate thereof.

Description

Technical Field
The present invention relates to a lymphocyte activation inhibitor. The present invention also relates to a therapeutic agent for an autoimmune disease, and more specifically to a therapeutic agent that is effective for rheumatism, multiple sclerosis, neuro-autoimmune diseases, type I (insulin-dependent) diabetes, systemic lupus erythematosus (SLE), inflammatory bowel diseases (IBD), and Sjogren's syndrome.
Background Art
It has been elucidated that division and activation of autoantigen-specific lymphocytes significantly contribute to aggravation of a pathological condition in autoimmune diseases. In other words, the autoantigen-specific lymphocytes get activated and proliferate by recognizing a part of the self as a foreign body, and induce disorders in tissues by causing activation of cells in other immune systems, thereby playing a significantly important role in the development of pathological conditions. Therefore, inhibiting the lymphocyte activation induced by an antigen allows the inhibition of development of an autoimmune disease. Specific examples of the autoimmune disease include rheumatism, multiple sclerosis, neuro-autoimmune diseases (Guillain-Barre syndrome, neuro-Behcet's disease, etc.), type I (insulin-dependent) diabetes, systemic lupus erythematosus (SLE), inflammatory bowel diseases (IBD), and Sjogren's syndrome, which are known as intractable diseases [reference document: Clinical Immunology and Immunopathology, 84, 223-243 (1997)].
Currently, lymphocyte activation inhibitors based on various action mechanisms have been clinically used for treatments of the autoimmune diseases described above. However, it is known that they accompany severe side effects in some cases, though their effectiveness are recognized. As a result, they have not been used widely, and the development of a lymphocyte activation inhibitor having a lower toxicity has been desired.
JP 07-165708 A, JP 08-231505 A, and JP 2000-247949 A disclose a sulfonamide compound or a sulfonic acid ester compound, whereas those publications describe nothing about the lymphocyte activation inhibition effect thereof.
Disclosure of the Invention
An object of the present invention is to provide a lymphocyte activation inhibitor having an excellent lymphocyte activation inhibition effect. Another object of the present invention is to provide a therapeutic agent for an autoimmune disease based on a lymphocyte activation inhibition effect.
In view of the above, the inventors of the present invention have made intensive studies for seeking an excellent lymphocyte activation inhibitor, and found that a sulfonamide compound and a sulfonic acid ester compound having a bicyclic hetero ring have an excellent lymphocyte activation inhibition effect and also have less toxicity, thus completing the present invention.
The present invention provides a lymphocyte activation inhibitor comprising, as an active ingredient, a sulfonamide derivative or sulfonic acid ester derivative represented by the following general formula (I):
Figure 00030001
wherein the ring A represents a monocyclic or bicyclic aromatic ring which may be substituted,
the ring B represents a 6-membered unsaturated hydrocarbon ring or a 6-membered unsaturated heterocyclic ring containing one nitrogen atom as a heteroatom, each of which may be substituted,
the ring C represents a 5-membered heterocyclic ring containing one or two nitrogen atoms, which may be substituted,
W represents a single bond or -CH=CH-,
X represents -N(R1)- or an oxygen atom,
Y represents a carbon atom or a nitrogen atom,
Z represents -N(R2)- or a nitrogen atom, and
R1 and R2 may be identical or different and each represents a hydrogen atom or a lower alkyl group, or a pharmacologically acceptable salt thereof, or a hydrate thereof.
The present invention also provides a therapeutic agent for an autoimmune disease, comprising, as an active ingredient, a sulfonamide derivative or sulfonic acid ester derivative represented by the above general formula (I), or a pharmacologically acceptable salt thereof, or a hydrate thereof.
In the general formula (I), it is preferred that W is a single bond. More preferably, X and Z are -NH-, and Y is a carbon atom.
In the general formula (I), it is preferred that the ring B is benzene or pyridine, each of which may be substituted.
In the general formula (I), it is preferred that the ring C is pyrrole which may be substituted.
In the general formula (I), it.is preferred that the ring A is benzene or pyridine, each of which may be substituted; the ring B is benzene which may be substituted; the ring C is pyrrole which may be substituted; W is a single bond; and X and Z are -NH-.
Examples of the autoimmune disease include cellular autoimmune diseases, rheumatism, multiple sclerosis, neuro-autoimmune diseases, type I (insulin-dependent) diabetes, systemic lupus erythematosus, inflammatory bowel diseases, and Sjogren's syndrome.
When the autoimmune disease is multiple sclerosis, it is preferred that the agent further comprises a drug having a neuron-protecting effect.
Brief Description of the Drawings
  • Fig. 1 shows effects on mouse collagen-induced arthritis.
  • Fig. 2 shows effects in an experimental encephalomyelitis model.
    • Best Mode for Carrying out the Invention
    In the general formula (I), the "monocyclic or bicyclic aromatic ring which may be substituted" represented by the ring A is an aromatic hydrocarbon ring or an aromatic heterocyclic ring containing at least one of nitrogen, oxygen and sulfur atoms, each of which may have one to three substituents thereon. Examples of such aromatic rings included in the ring A include pyrrole, pyrazole, imidazole, thiophene, furan, thiazole, oxazole, benzene, pyridine, pyrimidine, pyrazine, pyridazine, naphthalene, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, indole, isoindole, indolizine, indazole, benzofuran, benzothiophene, benzoxazole, benzimidazole, benzopyrazole, benzothiazole and so forth. They may have one to three substituents. When two or more substituents are present, they may be the same or different. Examples of the substituents include an amino group which may be substituted with a lower alkyl gourp or a lower cycloalkyl group; a lower alkyl group; a lower alkoxy group; hydroxyl; nitro; mercapto; cyano; a lower alkylthio group; a halogen group; a group represented by the formula -a-b wherein a represents a single bond, -(CH2)k-, -O-(CH2)k-, -S-(CH2)k- or -N(R3)-(CH2)k-, k is an integer of 1 to 5, R3 represents a hydrogen atom or a lower alkyl group, and b represents -CH2-d (wherein d represents an amino group which may be substituted with a lower alkyl group, a halogen group, hydroxyl, a lower alkylthio group, cyano or a lower alkoxy group); a group represented by the formula -a-e-f wherein a has the same meaning as defined above, e represents -S(O)- or -S(O)2-, f represents an amino group which may be substituted with a lower alkyl group or a lower alkoxy group, a lower alkyl group, trifluoromethyl, -(CH2)m-b or -N(R4)-(CH2)m-b (wherein b has the same meaning as defined above, R4 represents a hydrogen atom or a lower alkyl group, and m is an integer of 1 to 5); a group represented by the formula -a-g-h wherein a has the same meaning as defined above, g represents -C(O)- or -C(S)-, h represents an amino group which may be substituted with a lower alkyl group, hydroxyl, a lower alkyl group, a lower alkoxy group, - (CH2)n-b or -N(R5)-(CH2)n-b (wherein b has the same meaning as defined above, R5 represents a hydrogen atom or a lower alkyl group, and n is an integer of 1 to 5); a group represented by the formula -a-N(R6)-g-i wherein a and g have the same meanings as defined above, R6 represents a hydrogen atom or a lower alkyl group, i represents a hydrogen atom or a lower alkoxy group or f (f has the same meaning as defined above); a group represented by the formula -a-N(R7)-e-f wherein a, e and f have the same meanings as defined above, and R7 represents a hydrogen atom or a lower alkyl group; a group represented by the formula -(CH2)p-j-(CH2)q-b wherein j represents an oxygen atom or a sulfur atom, b has the same meaning as defined above, and p and q may be the same or different and each represents an integer of 1 to 5; a group represented by the formula -(CH2)u-Ar wherein Ar represents a phenyl group or a heteraryl group, which may be substituted with a lower alkyl group, a lower alkoxy group or a halogen atom and u represents 0 or an interger of 1 to 5; a group represented by the formula -CONH-(CH2)u-Ar wherein Ar and u have the same meaning as defined above; a group represented by the formula -SO2-(CH2)u-Ar wherein Ar and u have the same meaning as defined above; and so forth.
    When the substituent is an amino group substituted with two of alkyl groups, both of the alkyl groups may bond to form a 5- or 6-membered ring. Further, when the ring A is a nitrogen-containing heterocyclic ring having hydroxyl or mercapto, these groups may present in the form of an oxo or thioxo group by resonance.
    The "6-membered unsaturated hydrocarbon ring or 6-membered unsaturated heterocyclic ring containing one nitrogen atom as a heteroatom, which may be substituted" represented by the ring B means benzene or pyridine which may be partially hydrogenated. It may have one or two of substituents on the ring, and when two of substituents are present, they may be the same or different.
    The "5-membered heterocyclic ring containing one or two nitrogen atoms, which may be substituted" represented by the ring C means pyrrole, pyrazole or imidazole which may be partially hydrogenated. It may have one or two of substituents on the ring, and when two of substituents are present, they may be the same or different.
    Examples of the substituents that the rings of B and C may have include a halogen group, cyano, a lower alkyl group, a lower alkoxy group, hydroxyl, oxo, a group represented by the formula -C(O)-r (wherein r represents a hydrogen atom, an amino group which may be substituted with a lower alkyl group, a lower alkyl group, a lower alkoxy group or hydroxyl), an amino group substituted with a lower alkyl group, trifluoromethyl and so forth.
    In the general formula (I), the lower alkyl group in the definitions of R1 and R2 as well as the substituents that the rings of A, B and C may have means a linear or branched alkyl group having 1 to 6 carbon atoms, and examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl (amyl), isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl and so forth. Among these, methyl,. ethyl, n-propyl, isopropyl, n-butyl and isobutyl are preferred, and methyl, ethyl, n-propyl and isopropyl are most preferred.
    The lower cycloalkyl group mentioned in the definitions of the substituents that the ring of A may have means a cycloalkyl group having 3 to 8 carbon atoms, and examples thereof include cyclopropyl, cyclopentyl, cyclohexyl and so forth.
    The lower alkoxy mentioned in the definitions of the substituents that the rings of A, B and C may have means an alkoxyl' group derived from the aforementioned lower alkyl group, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. Among these, methoxy and ethoxy are most preferred. The lower alkylthio group means an alkylthio group derived from the aforementioned lower alkyl group. Further, examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and so forth.
    The sulfonamide derivatives or the sulfonic acid ester derivatives represented by the general formula (I) may form a salt with an acid or a base. The active ingredient used in the present invention also includes salts of the sulfonamide derivatives or the sulfonic acid ester represented by the general formula (I). Examples of the salt with an acid include salts with inorganic acids, such as hydrochlorides, hydrobromides and sulfates, and salts with organic acids such as acetic acid, lactic acid, succinic acid, fumaric acid, maleic acid, citric acid, benzoic acid, methanesulfonic acid and p-toluenesulfonic acid. Examples of the salt with a base include salts with inorganic bases, such as sodium salts, potassium salts and calcium salts and salts with organic bases such as triethylamine, arginine and lysine.
    It is needless to say that the compounds include hydrates and optical isomers of these compounds if they are present.
    A list of specific examples of the sulfonamide derivative or the sulfonic acid ester derivative represented by the general formula (I) or the pharmacologically acceptable salt, or the hydrate thereof is as follows:
  • Compound 1
    N-(1H-Indol-7-yl)-4-nitrobenzenesulfonamide
  • Compound 2
    N-(3-Chloro-1H-indol-7-yl)-4-nitrobenzenesulfonamide
  • Compound 3
    4-Amino-N-(3-chloro-1H-indol-7-yl)benzenesulfonamide
  • Compound 4
    N-(3-Chloro-1H-indol-7-yl)-4-(methanesulfonamido)-benzenesulfonamide
  • Compound 5
    4-Bromomethyl-N-(1H-indol-7-yl)benzenesulfonamide
  • Compound 6
    N-(1,3-Dihydro-2H-indol-2-on-7-yl)-4-methylbenzenesulfonamide
  • Compound 7
    3-Chloro-N-(3-chloro-1H-indol-7-yl)benzenesulfonamide
  • Compound 8
    4-Amino-N-(3,4-dichloro-1H-indol-7-yl)benzenesulfonamide
  • Compound 9
    4-[N-(1H-Indol-7-yl)sulfamoyl]benzoic acid
  • Compound 10
    N-(3-Chloro-1H-indol-7-yl)-4-cyanobenzenesulfonamide
  • Compound 11
    3-Chloro-N-(3-chloro-4-methoxy-1H-indol-7-yl)-benzenesulfonamide
  • Compound 12
    3-Chloro-N-(3-chloro-4-hydroxy-1H-indol-7-yl)-benzenesulfonamide
  • Compound 13
    N-(1H-Indol-7-yl)-4-methoxybenzenesulfonamide
  • Compound 14
    6-Chloro-N-(3-chloro-1H-indol-7-yl)-3-pyridinesulfonamide
  • Compound 15
    N-(3-Chloro-1H-indol-7-yl)-4-(methylthiomethyl)-benzenesulfonamide
  • Compound 16
    3-Chloro-N-(3-formyl-1H-indol-7-yl)benzenesulfonamide
  • Compound 17
    3-Chloro-N-(3-cyano-1H-indol-7-yl)benzenesulfonamide
  • Compound 18
    6-Chloro-N-(3-cyano-1H-indol-7-yl)-3-pyridinesulfonamide
  • Compound 19
    N-(3-Chloro-1H-indol-7-yl)-4-sulfamoylbenzenesulfonamide
  • Compound 20
    3-Chloro-N-(8-imidazo[1,2-a]pyridinyl)benzenesulfonamide hydrochloride
  • Compound 21
    N-(3,4-Dichloro-1H-indol-7-yl)-4-sulfamoylbenzenesulfonamide
  • Compound 22
    N-(3-Chloro-1H-indol-7-yl)-4-(methylthio)benzenesulfonamide
  • Compound 23
    N-(3-Chloro-1H-indol-7-yl)-4-(methylsulfonyl)-benzenesulfonamide
  • Compound 24
    N-(3-Chloro-1H-indol-7-yl)-4-(methylsulfinyl)-benzenesulfonamide
  • Compound 25
    3-Chlorb-N-(3-chloro-1H-pyrrolo[3,2-c]pyridin-7-yl)-benzenesulfonamide
  • Compound 26
    4-Acetamido-N-(3-chloro-4-methyl-1H-indol-7-yl)-benzenesulfonamide
  • Compound 27
    4-Amino-N-(3-chloro-4-methyl-1H-indol-7-yl)-benzenesulfonamide
  • Compound 28
    4-Cyano-N-(3-chloro-1H-indol-7-yl)benzenesulfonamide
  • Compound 29
    4-Carbamoyl-N-(3-chloro-1H-indol-7-yl)benzenesulfonamide
  • Compound 30
    N-(4-Bromo-1H-indol-7-yl)-4-nitrobenzenesulfonamide
  • Compound 31
    N-(3-Chloro-4-cyano-1H-indol-7-yl)-4-nitrobenzenesulfonamide
  • Compound 32
    4-Amino-N-(3-chloro-4-cyano-1H-indol-7-yl)-benzenesulfonamide
  • Compound 33
    4-Amino-N-(3-chloro-1H-indol-7-yl)-3-pyridinesulfonamide
  • Compound 34
    N-(3-Chloro-1H-indol-7-yl)-4-(methylsulfinylmethyl)-benzenesulfonamide
  • Compound 35
    N-(3-Chloro-1H-indol-7-yl)-4-(2-sulfamoylethyl)-benzenesulfonamide
  • Compound 36
    N-(3-Chloro-1H-indol-7-yl)-4-[2-(methylsulfonyl)ethyl]-benzenesulfonamide
  • Compound 37
    6-Amino-N-(3-cyano-1H-indol-7-yl)-3-pyridinesulfonamide
  • Compound 38
    4-Acetamide-3-chloro-N-(3-chloro-1H-indol-7-yl)-benzenesulfonamide
  • Compound 39
    N-(3-Cyano-1H-indol-7-yl)-8-quinolinesulfonamide
  • Compound 40
    5-Chloro-N-(3-cyano-1H-indol-7-yl)-2-thiophenesulfonamide
  • Compound 41
    N-(3-Chloro-1H-indol-7-yl)-4-(methoxycarbonylamino)-benzenesulfonamide
  • Compound 42
    4-Acetyl-N-(3-cyano-1H-indol-7-yl)benzenesulfonamide
  • Compound 43
    N-(3-Chloro-1H-indol-7-yl)-4-(N-methoxysulfamoyl)-benzenesulfonamide
  • Compound 44
    N-(3-Cyano-1H-indol-7-yl)-β-styrenesulfonamide
  • Compound 45
    3-Chloro-N-(3-cyano-1H-indol-7-yl)-2-methylbenzenesulfonamide
  • Compound 46
    N-(3-Chloro-1H-indol-7-yl)-6-isopropylamino-3-pyridinesulfonamide
  • Compound 47
    N-(3-Chloro-1H-indol-7-yl)-6-[[2-(dimethylamino)-ethyl]amino]-3-pyridinesulfonamide
  • Compound 48
    N-(3-Cyano-1H-indol-7-yl)-2-furansulfonamide
  • Compound 49
    N-(3-Chloro-1H-indol-7-yl)-4-[(dimethylaminosulfonyl)-amino]benzenesulfonamide
  • Compound 50
    N-(3-Methyl-1H-indol-7-yl)-4-(methylsulfonyl)-benzenesulfonamide
  • Compound 51
    3-Cyano-N-(3-cyano-1H-indol-7-yl)benzenesulfonamide
  • Compound 52
    N-(3-Chloro-1H-indol-7-yl)-4-(N-methylmethanesulfonamido)-benzenesulfonamide
  • Compound 53
    N-(3-Chloro-1H-indol-7-yl)-4-[(methanesulfonamido)methyl]-benzenesulfonamide
  • Compound 54
    N-(3-Chloro-lH-indol-7-yl)-4-(1-pyrrolidinylsulfonyl)-benzenesulfonamide
  • Compound 55
    N-(3-Cyano-1H-indol-7-yl)-1-methyl-4-imidazolesulfonamide
  • Compound 56
    N-(3-Chloro-1H-indol-7-yl)-6-[(2-hydroxyethyl)amino]-3-pyridinesulfonamide
  • Compound 57
    N-(3-Chloro-1H-indol-7-yl)-6-mercapto-3-pyridinesulfonamide
  • Compound 58
    7-(4-Chlorobenzenesulfonamido)-1H-indole-2-carboxylic acid
  • Compound 59
    N-(3-Chloro-1H-indol-7-yl)-6-cyclopropylamino-3-pyridinesulfonamide
  • Compound 60
    N-(3-Cyano-1H-indol-7-yl)-5-methyl-3-pyridinesulfonamide
  • Compound 61
    N-(3-Chloro-1H-indol-7-yl)-4-(N-methylsulfamoyl)-benzenesulfonamide
  • Compound 62
    N-(3-Chloro-1H-indol-7-yl)-4-[2-(methanesulfonamido)ethyl]-benzensulfonamide
  • Compound 63
    N-(3-Chloro-1H-indol-7-yl)-4-(sulfamoylmethyl)-benzensulfonamide
  • Compound 64
    N-(3-Chloro-1H-indol-7-yl)-4-thiocarbamoylbenzensulfonamide
  • Compound 65
    5-Bromo-N-(3-cyano-1H-indol-7-yl)-2-pyridinesulfonamide
  • Compound 66
    N-(3-Cyano-1H-indol-7-yl)-2-naphthalenesulfonamide
  • Compound 67
    N-(3-Acetyl-1H-indol-7-yl)-3-chlorobenzenesulfonamide
  • Compound 68
    4-Amino-N-(5-bromo-3-cyano-1H-indol-7-yl)benzenesulfonamide
  • Compound 69
    N-(3-Chloro-1H-indol-7-yl)-4-(N-ethylsulfamoyl)-benzenesulfonamide
  • Compound 70
    N-(3-Chloro-1H-indol-7-yl)-4-(ethanesulfonamido)-benzenesulfonamide
  • Compound 71
    N-(3-Chloro-1H-indol-7-yl)-6-[(2-cyanoethyl)amino]-3-pyridinesulfonamide
  • Compound 72
    N-(3-Chloro-1H-indol-7-yl)-4-(N-methylcarbamoyl)-benzenesulfonamide
  • Compound 73
    N-(3-Chloro-lH-indol-7-yl)-4-(methylsulfonylmethyl)-benzenesulfonamide
  • Compound 74
    N-(3-Chloro-1H-indol-7-yl)-4-(N,N-dimethylsulfamoyl)-benzenesulfonamide
  • Compound 75
    N-(3-Chloro-1H-indol-7-yl)-4-(1-pyrrolidinylcarbonyl)-benzenesulfonamide
  • Compound 76
    3-Chloro-N-(3-chloro-1H-indol-7-yl)-N-methylbenzenesulfonamide
  • Compound 77
    N-(3,4-Dichloro-1H-indol-7-yl)-4-(sulfamoylmethyl)-benzenesulfonamide
  • Compound 78
    N-(3-Cyano-1H-indol-7-yl)-4-[2-(methylsulfonyl)ethyl]-benzenesulfonamide
  • Compound 79
    N-(3-Chloro-1H-indol-7-yl)-4-(N-methylacetamido)-benzenesulfonamide
  • Compound 80
    N-(3-Chloro-1H-indol-7-yl)-6-hydroxy-3-pyridinesulfonamide
  • Compound 81
    N-(3-Chloro-1H-indol-7-yl)-4-[2-(N-methylmethanesulfonamido)ethyl]benzenesulfonamide
  • Compound 82
    N-(3-Chloro-1H-indol-7-yl)-4-(trifluoromethanesulfonamido)benzenesulfonamide
  • Compound 83
    N-(3-Chloro-1H-indol-7-yl)-4-[(N-methylmethanesulfonamido)methyl]benzenesulfonamide
  • Compound 84
    3-Chloro-N-(3-chloro-1H-pyrrolo[2,3-c]pyridin-7-yl)-benzenesulfonamide
  • Compound 85
    4-(3-Bromopropyl)-N-(3-chloro-1H-indol-7-yl)-benzenesulfonamide
  • Compound 86
    4-[N-(2-Bromoethyl)sulfamoyl]-N-(3-chloro-1H-indol-7-yl)-benzenesulfonamide
  • Compound 87
    N-(3-Chloro-1H-indol-7-yl)-4-[3-(1-imidazolyl)propyl]-benzenesulfonamide
  • Compound 88
    N-(3-Chloro-1H-indol-7-yl)-4-[N-(2-(2-pyridinyl)ethyl)-carbamoyl]benzenesulfonamide
  • Compound 89
    4-Amidino-N-(3-chloro-1H-indol-7-yl)benzenesulfonamide
  • Compound 90
    N-(3-Chloro-1H-indol-7-yl)-4-[N-[2-(1-imidazolyl)ethyl]-sulfamoyl]benzenesulfonamide
  • Compound 91
    3-(5-Bromonicotinamido)-N-(3-cyano-1H-indol-7-yl)-benzenesulfonamide
  • Compound 92
    N-(3-Chloro-1H-indol-7-yl)-4-[N-(2-thiazolyl)sulfamoyl]-benzenesulfonamide
  • Compound 93
    5-Chloro-N-(3-chloro-1H-indol-7-yl)-4-(5-methyl-3-pyridinesulfonamido)-2-thiophenesulfonamide
  • Compound 94
    3-Cyano-N-(3-cyano-4-methyl-1H-indol-7-yl)-benzenesulfonamide
    • The sulfonamide derivative or the sulfonic acid ester derivative represented by the general formula (I), a pharmacologically acceptable salt thereof, or a hydrate of the same (hereinafter, also referred as "the compound represented by the general formula (I)") may be manufactured by various methods. Among them, representative methods are described in JP 07-165708 A, JP 08-231505 A, and JP 2000-247949 A.
    The compound represented by the general formula (I) has an excellent lymphocyte activation inhibition effect. Thus, the compound represented by the general formula (I) may be used as an active ingredient for a lymphocyte activation inhibitor. It may also be used as an active ingredient of a therapeutic agent for diseases in which inhibition of lymphocyte activation is effective to treatment thereof. Thus, according to the present invention, there is provided a method for inhibiting lymphocyte activation, comprising administering an effective amount of the compound represented by the general formula (I); and a method for treating a disease in which inhibition of lymphocyte activation is effective to treatment thereof, comprising administering an effective amount of the compound represented by the general formula (I). Also, according to the present invention, there is provided a use of the compound represented by the general formula (I) in manufacture of a lymphocyte activation inhibitor, and a use of the compound represented by the general formula (I) in manufacture of a therapeutic agent for a disease in which inhibition of lymphocyte activation is effective to treatment thereof.
    The phrase "the compound represented by the general formula (I) as an active ingredient" includes a compound that generates the compound represented by the general formula (I) due to in vivo metabolism such as oxidation, reduction, and hydrolysis.
    Similarly, the phrases "administering the compound represented by the general formula (I)" and "use of the compound represented by the general formula (I)" in the present invention also include administering and using a compound which generates the compound represented by the general formula (I) due to in vivo metabolism such as oxidation, reduction, and hydrolysis, respectively.
    In the present invention, the word "treatment" also includes alleviating a symptom of a disease.
    Examples of the disease in which inhibition of lymphocyte activation is effective to treatment thereof include autoimmune diseases. Examples of the autoimmune diseases include rheumatism, multiple sclerosis, neuro-autoimmune diseases (Guillain-Barre syndrome, neuro-Behcet's disease, etc.), type I (insulin-dependent) diabetes, systemic lupus erythematosus (SLE), inflammatory bowel diseases (IBD), and Sjogren's syndrome, etc.
    The compound represented by the general formula (I) may be used in a preparation made by a general method. For example, it may be a composition with a carrier (if used for a medicine, a pharmacologically acceptable carrier).
    The compound represented by the general formula (I), if used as a medicine, is administered orally or parenterally. The dose is different depending on degree of a symptom, age of a patient, sex, body weight, sensibility difference, administration method, administration timing, administration interval, medicinal characteristics, preparation, allegation, type, type of active ingredient, or the like. The dose is generally 10 to 6,000 mg, preferably about 50 to 4,000 mg, more preferably 100 to 3,000 mg per day for an adult, which was separately administered generally 1 to 3 time(s) in a day, but there is no particular limitation thereto.
    In order to prepare an oral solid dosage form, a vehicle and optionally with a binder, disintegrator, lubricant, colorant, corrective, etc. are added to a base, and a mixture thereof is then treated in accordance with a conventional method to form tablets, coated tablets, granules, fine granules, powder, capsules, etc.
    Examples of the vehicle include lactose, cornstarch, saccharose, glucose, sorbitol, crystalline cellulose, and silicon dioxide. Examples of the binder include polyvinyl alcohol, ethylcellulose, methylcellulose, acacia gum, hydroxypropylcellulose, and hydroxypropylmethylcellulose. Examples of the lubricant include magnesium stearate, talc, and silica. As the colorant, one permitted to add to a drug is used. Examples of the corrective include cocoa powder, menthol, aromatic acid, peppermint oil, borneol, and cinnamon powder. As a matter of course, those tablets and granules may optionally be coated appropriately with sugar, gelatin, etc.
    In order to prepare an injection, a pH regulator, a buffer, a suspending agent, a solubilizer, a stabilizer, an isotonizing agent, a preservative, etc. are optionally added to a base, and a mixture thereof is then treated in accordance with a conventional method to form an injection for intravenous, hypodermic, or intramuscular injection. The injection may optionally be treated in accordance with a conventional method to form a freeze-dry product.
    Examples of the suspending agent include methylcellulose, polysorbate 80, hydroxyethylcellulose, acacia gum, tragacanth powder, sodium carboxymethylcellulose, and polyoxyethylenesorbitan monolaurate.
    Examples of the solubilizing agent include polyoxyethylene hardened castor oil, polysorbate 80, nicotinic acid amide, polyoxyethylenesorbitan monolaurate, macrogol, and castor oil fatty acid ethyl ester.
    Examples of the stabilizer include sodium sulfite and sodium metasulfite. Examples of the preservative include methyl paraoxybenzoate, ethyl paraoxybenzoate, sorbic acid, phenol, cresol, and chlorocresol.
    If the autoimmune disease is multiple sclerosis, the therapeutic agent for an autoimmune disease is preferred to further include a drug having a neuron-protecting effect.
    The neuron-protecting effect means an effect of inhibiting a morbid change such as nerve axonal degeneration in multiple sclerosis by directly effecting to nerves.
    Examples of the drug having a neuron-protecting effect include a glutamic acid antagonist, a sodium channel antagonist, a calcium channel antagonist, etc.
    The compound represented by the general formula (I) and the drug having a neuron-protecting effect may be mixed or separately encased to be packed in a unit.
    The compound represented by the general formula (I) and the drug having a neuron-protecting effect may be administered simultaneously or in order.
    Examples
    The effect of the compound used in the present invention will now be shown with reference to pharmacological experimental examples.
    Pharmacological experimental example 1: Inhibition effect for lymphocyte activation
    Immunizing a mouse with a partial peptide of a proteolipid protein (PLP), a central myelin protein, induces a chronic encephalomyelitis therein. Sampling lymphocytes from the spleen of the mouse and stimulating by an antigen in vitro allow the induction of antigen-specific activation and division of the lymphocyte. The effect of a drug to the reaction was examined to evaluate the inhibition effect of the drug for lymphocyte activation. Specifically, a female SJL/J mouse was immunized with an adjuvant containing a PLP partial peptide (PLP139-151) under ether anesthesia. On the day of immunization and 2 days thereafter, deactivated Bordetella pertussis (one billion/mouse) was intravenously administered. On 7th or 8th day after the immunization, the mouse was killed by ether anesthesia and then the spleen thereof was extracted to isolate spleen lymphocytes. The lymphocytes were cultured with the PLP139-151 in a medium containing 10% bovine fetal serum at 37°C under 5% CO2 for 5 days. 3H-Thymidine (0.5 µCi/well) was added 16 hours before terminating the culture, and then radioactivity in the cells was measured to evaluate the inhibition effect of the compound for antigen-specific division of the lymphocytes, which was' referred as an IC50 value. The experimental results are shown in Table 1. The compound numbers are the same as those described in the previous list (hereinafter, the same).
    Compound No. IC50 (micro M) Compond No. IC50 (micro M)
    3 2.27 37 0.64
    4 1.43 51 0.62
    10 0.59 53 0.74
    17 0.44 62 0.58
    19 1.83 69 0.59
    28 2.86 70 1.40
    29 1.01 72 1.81
    33 0.47 77 0.98
    35 0.67 79 0.36
    36 0.78 94 0.25
    Pharmacological experimental example 2: Effect on mouse collagen-induced arthritis
    A DBA/1JN male mouse (7 weeks of age) was sensitized by intracutaneously injecting in the tail part thereof with 0.1 ml of an emulsion solution obtained by mixing a 0.3% bovine-derived type II collagen solution with the same amount of a Freund's complete adjuvant. After 3 weeks after initial sensitization, a booster was conducted in a similar way to cause arthritis. The subjective compound was made into a solution (5 mg/ml) according to a general method, and the day of the booster and 3 days thereafter, the solution was intravenously administered in an amount of 10 ml/kg (50 mg/kg). In experiments, 8 mice were used for each of a control group and a drug-administered group. The condition of arthritis was evaluated macroscopically on limbs and graded into 5 score levels (0; normal, 1; flare on a finger joint, 2; slight' edema on an entire leg, 3; edema on an entire leg, and 4; severe edema on an entire leg), to be shown as a total sum. As a result of the experiment using the Compound 19, the compound had an obvious inhibition effect for the crisis and development of arthritis. The effect lasted even after the second administration and the inhibition effect was recognized even 36 days after the initial sensitization, i.e., 12 days after administration (Fig. 1).
    Note that, the mouse collagen-induced arthritis model described above is a model in which a lymphocyte activated by reacting with an immunized collagen recognizes an autotissue, particularly collagen in a joint tissue and causes an immunoreaction to induce arthritis, and is widely recognized as a model for evaluating a pharmacological. effect of a compound having a lymphocyte activation inhibition effect (e.g., Br. J. Rheumatol., 33, 798 (1994)). Pharmacological experimental example 3: Effect in an experimental encephalomyelitis model
    100 µl of a Freund's complete adjuvant (Difco, containing 0.6 mg/ml of M. tuberculosis H37Ra) containing the PLP peptide (p139-151, Toray Research Center) was subcutaneously injected to a female SJL/J mouse in the back thereof under ether anesthesia for immunization (initial sensitization). Two days after, deactivated Bordetella pertussis was intravenously injected in an amount of about one billion per mouse. Seven days after, immunization was conducted again with the antigen. Over several weeks thereafter, abnormalities in limbs, a tail, and righting reflexes were graded into scored levels and recorded. The subjective compound was orally administered in an amount of 200 mg/kg from 5th day to 12th day after the initial sensitization. In experiments, 12 mice were used for each of a control group and a drug-administered group. As a result of experiments using the compounds shown in the Compounds 10 and 17 as subjective compounds, those compounds delayed expression of abnormality appeared in the mice, and alleviated the severity (Fig. 2).
    Note that, the experimental encephalomyelitis model described above is a model in which a lymphocyte activated by reacting with an immunized PLP peptide causes an immunoreaction to induce encephalomyelitis, and is widely recognized as a model for evaluating a pharmacological effect of a compound having a lymphocyte activation inhibition effect (e.g., Agents and Actions, 27, 351-355 (1989); and Agents and Actions, 35, 79-84 (1992)).
    As is apparent from the above experimental examples, the compound represented by the general formula (I) has an excellent lymphocyte activation inhibition effect. It is therefore considered to be useful as a therapeutic agent for autoimmune diseases, for treatment of rheumatism, multiple sclerosis, neuro-autoimmune diseases (Guillain-Barre syndrome, neuro-Behcet's disease, etc.), type I (insulin-dependent) diabetes, systemic lupus erythematosus (SLE), inflammatory bowel diseases (IBD), and Sjogren's syndrome, etc.
    Moreover, even when the Compounds 10, 17, 51, and 94 were administered to mice successively for 15 days in amounts of 100 mg/kg and 200 mg/kg, respectively, the conditions of the mice were quite normal with dose-dependent weight increases and there was no observation showing toxicity. It is thus considered that the compound represented by the general formula (I) has low toxicity.
    Industrial Applicability
    A lymphocyte activation inhibitor and a therapeutic agent for an autoimmune disease are provided.

    Claims (14)

    1. A lymphocyte activation inhibitor comprising, as an active ingredient, a sulfonamide derivative or sulfonic acid ester derivative represented by the following general formula (I):
      Figure 00280001
      wherein the ring A represents a monocyclic or bicyclic aromatic ring which may be substituted,
      the ring B represents a 6-membered unsaturated hydrocarbon ring or a 6-membered unsaturated heterocyclic ring containing one nitrogen atom as a heteroatom, each of which may be substituted,
      the ring C represents a 5-membered heterocyclic ring containing one or two nitrogen atoms, which may be substituted,
      W represents a single bond or -CH=CH-,
      X represents -N(R1)- or an oxygen atom,
      Y represents a carbon atom or a nitrogen atom,
      Z represents -N(R2)- or a nitrogen atom, and
      R1 and R2 may be identical or different and each represents a hydrogen atom or a lower alkyl group, or a pharmacologically acceptable salt thereof, or a hydrate thereof.
    2. The lymphocyte activation inhibitor according to claim 1, wherein W is a single bond.
    3. The lymphocyte activation inhibitor according to claim 2, wherein X and Z are -NH-, and Y is a carbon atom.
    4. The lymphocyte activation inhibitor according to any one of claims 1 to 3, wherein the ring B is benzene or pyridine, each of which may be substituted.
    5. The lymphocyte activation inhibitor according to any one of claims 1 to 4, wherein the ring C is pyrrole which may be substituted.
    6. The lymphocyte activation inhibitor according to claim 1, wherein the ring A is benzene or pyridine, each of which may be substituted; the ring B is benzene which may be substituted; the ring C is pyrrole which may be substituted; W is a single bond; and X and Z are -NH-.
    7. A therapeutic agent for an autoimmune disease, comprising, as an active ingredient, a sulfonamide derivative or sulfonic acid ester derivative represented by the following general formula (I):
      Figure 00290001
      wherein the ring A represents a monocyclic or bicyclic aromatic ring which may be substituted,
      the ring B represents a 6-membered unsaturated hydrocarbon ring or a 6-membered unsaturated heterocyclic ring containing one nitrogen atom as a heteroatom, each of which may be substituted,
      the ring C represents a 5-membered heterocyclic ring containing one or two nitrogen atoms, which may be substituted,
      W represents a single bond or -CH=CH-,
      X represents -N(R1)- or an oxygen atom,
      Y represents a carbon atom or a nitrogen atom,
      Z represents -N(R2)- or a nitrogen atom, and
      R1 and R2 may be identical or different and each represents a hydrogen atom or a lower alkyl group, or a pharmacologically acceptable salt thereof, or a hydrate thereof.
    8. The therapeutic agent according to claim 7, wherein W is a single bond.
    9. The therapeutic agent according to claim 8, wherein X and Z are -NH-, and Y is a carbon atom.
    10. The therapeutic agent according to any one of claims 7 to 9, wherein the ring B is benzene or pyridine, each of which may be substituted.
    11. The therapeutic agent according to any one of claims 7 to 10, wherein the ring C is pyrrole which may be substituted.
    12. The therapeutic agent according to claim 7, wherein the ring A is benzene or pyridine, each of which may be substituted; the ring B is benzene which may be substituted; the ring C is pyrrole which may be substituted; W is a single bond; and X and Z are -NH-.
    13. The therapeutic agent according to any one of claims 7 to 12, wherein the autoimmune disease is a disease selected from the group consisting of cellular autoimmune diseases, rheumatism, multiple sclerosis, neuro-autoimmune diseases, type I (insulin-dependent) diabetes, systemic lupus erythematosus, inflammatory bowel diseases, and Sjogren's syndrome.
    14. The therapeutic agent according to claim 13, wherein the autoimmune disease is multiple sclerosis, and the agent further comprises a drug having a neuron-protecting effect.
    EP02798032A 2001-09-05 2002-09-05 Lymphocytic activation inhibitor and remedial agent for autoimmune disease Withdrawn EP1430894A4 (en)

    Applications Claiming Priority (3)

    Application Number Priority Date Filing Date Title
    JP2001269480 2001-09-05
    JP2001269480 2001-09-05
    PCT/JP2002/009030 WO2003022271A1 (en) 2001-09-05 2002-09-05 Lymphocytic activation inhibitor and remedial agent for autoimmune disease

    Publications (2)

    Publication Number Publication Date
    EP1430894A1 true EP1430894A1 (en) 2004-06-23
    EP1430894A4 EP1430894A4 (en) 2007-12-12

    Family

    ID=19095292

    Family Applications (1)

    Application Number Title Priority Date Filing Date
    EP02798032A Withdrawn EP1430894A4 (en) 2001-09-05 2002-09-05 Lymphocytic activation inhibitor and remedial agent for autoimmune disease

    Country Status (6)

    Country Link
    US (1) US20040235866A1 (en)
    EP (1) EP1430894A4 (en)
    JP (1) JPWO2003022271A1 (en)
    CN (1) CN1551766A (en)
    TW (1) TW589181B (en)
    WO (1) WO2003022271A1 (en)

    Cited By (2)

    * Cited by examiner, † Cited by third party
    Publication number Priority date Publication date Assignee Title
    EP1873144A4 (en) * 2005-04-20 2009-05-06 Takeda Pharmaceutical FUSIONED HETEROCYCLIC COMPOUND
    US7939519B2 (en) 2003-05-19 2011-05-10 Novartis Ag Immunosuppresant compounds and compositions

    Families Citing this family (4)

    * Cited by examiner, † Cited by third party
    Publication number Priority date Publication date Assignee Title
    US7521472B2 (en) 2004-11-17 2009-04-21 Eisai R&D Management Co., Ltd. Crystal of two-ring heterocyclic sulfonamide compound
    WO2006090932A1 (en) * 2005-02-28 2006-08-31 Eisai R & D Managemant Co., Ltd. Surrogate marker for sulfonamide compound
    DE102007035333A1 (en) * 2007-07-27 2009-01-29 Boehringer Ingelheim Pharma Gmbh & Co. Kg Novel substituted arylsulfonylglycines, their preparation and their use as pharmaceuticals
    DE102007035334A1 (en) * 2007-07-27 2009-01-29 Boehringer Ingelheim Pharma Gmbh & Co. Kg Novel substituted arylsulfonylglycines, their preparation and their use as pharmaceuticals

    Family Cites Families (13)

    * Cited by examiner, † Cited by third party
    Publication number Priority date Publication date Assignee Title
    JPS5589222A (en) * 1978-12-28 1980-07-05 Otsuka Pharmaceut Co Ltd Antihistaminic agent
    WO1995007276A1 (en) * 1993-09-10 1995-03-16 Eisai Co., Ltd. Bicyclic heterocyclic sulfonamide and sulfonic ester derivatives
    JP3545461B2 (en) * 1993-09-10 2004-07-21 エーザイ株式会社 Bicyclic heterocycle-containing sulfonamide derivatives
    US5939431A (en) * 1996-06-20 1999-08-17 Schering Corporation Naphthyridines which affect IL-4 and G-CSF
    DE69730137T2 (en) * 1996-06-20 2005-07-14 Schering Corp. NAPHTHYRIDINES INFLUENCING THE RECEPTOR IL-4 AND THE FACTOR G-CSF
    WO1998018076A1 (en) * 1996-10-18 1998-04-30 Intervu, Inc. System and method for optimized storage and retrieval of data on a distributed computer network
    PT1021413E (en) * 1997-10-06 2003-10-31 Wyeth Corp THE PREPARATION AND UTILIZATION OF HYDROXAMIC BICYCLIC HETEROCYCLIC ACIDS ORTHOSULPONAMIDES AS MATRIX AND TACE METALOPROTEINES INHIBITORS
    JP2000247949A (en) * 1999-02-26 2000-09-12 Eisai Co Ltd Indole compound containing sulfonamide
    JP4007743B2 (en) * 1999-02-26 2007-11-14 エーザイ・アール・アンド・ディー・マネジメント株式会社 Angiogenesis inhibitor
    CN1891693A (en) * 2000-01-24 2007-01-10 基纳西亚股份有限公司 Therapeutic morpholino-substituted compounds
    MXPA02007249A (en) * 2000-02-03 2002-12-09 Eisai Co Ltd Integrin expression inhibitors.
    JP2002167376A (en) * 2000-11-30 2002-06-11 Mercian Corp Indole derivatives having vascular endothelial cell growth factor expression inhibitory action and uses thereof
    ATE412895T1 (en) * 2001-02-21 2008-11-15 Eisai R&D Man Co Ltd METHOD FOR STUDYING THE EFFECT OF AN ANGIOGENESIS INHIBITOR MEDIATED BY INHIBITION OF INTEGRIN EXPRESSION

    Cited By (4)

    * Cited by examiner, † Cited by third party
    Publication number Priority date Publication date Assignee Title
    US7939519B2 (en) 2003-05-19 2011-05-10 Novartis Ag Immunosuppresant compounds and compositions
    EP1873144A4 (en) * 2005-04-20 2009-05-06 Takeda Pharmaceutical FUSIONED HETEROCYCLIC COMPOUND
    EP2308839A1 (en) * 2005-04-20 2011-04-13 Takeda Pharmaceutical Company Limited Fused heterocyclic compounds
    US8957070B2 (en) 2005-04-20 2015-02-17 Takeda Pharmaceutical Company Limited Glucokinase activator compounds, methods of activating glucokinase and methods of treating diabetes and obesity

    Also Published As

    Publication number Publication date
    CN1551766A (en) 2004-12-01
    WO2003022271A1 (en) 2003-03-20
    US20040235866A1 (en) 2004-11-25
    TW589181B (en) 2004-06-01
    EP1430894A4 (en) 2007-12-12
    JPWO2003022271A1 (en) 2004-12-24

    Similar Documents

    Publication Publication Date Title
    US7919484B2 (en) Combination therapy
    AU2011235301B2 (en) Uses of DGAT1 inhibitors
    JP4399862B2 (en) Treatment for bowel disease and visceral pain
    KR20060010717A (en) Novel Arylpiperazinyl Compounds
    BRPI0609464A2 (en) pyrazole compound and therapeutic agent for diabetes comprising the same
    TW202045497A (en) A method for treating fatty liver diseases and/or fatty liver hepatitis
    US20230059381A1 (en) Prophylactic or therapeutic agent for neuropathic pain associated with guillain-barre syndrome
    AU2016256923A1 (en) Methods of treating a neurodegenerative disease
    ZA200308110B (en) Use of nk-1 receptor antagonists against benign prostatic hyperplasia
    NZ500343A (en) Peripherally acting anti-pruritic opiates
    EP1430894A1 (en) Lymphocytic activation inhibitor and remedial agent for autoimmune disease
    US7015241B2 (en) Appetite-stimulating agents and remedies for anorexia
    CN1930123B (en) Pharmaceutical composition for preventing or treating overactive bladder accompanied by neurological disorder
    JPWO2011058943A1 (en) Pharmaceutical composition comprising a combination of a compound having MCHR1 antagonist activity and a compound having NPYY5 receptor antagonist activity
    RU2379305C2 (en) Thiomorpholine compound and method for making thereof
    US10759768B2 (en) Prophylactic or therapeutic agent for autism spectrum disorder
    US20250361243A1 (en) Compounds and Pharmaceutical Compositions Useful for Managing Sickle Cell Disease and Conditions Related Thereto
    CN119584967A (en) Compositions and methods for treating hepatic porphyria using glycine transport inhibitors
    JP2004137267A (en) Rheumatic drug containing benzamide derivative as active ingredient
    WO2026067383A1 (en) Imidazopyridine derivative and use thereof
    HK40096733A (en) Therapeutic agent for gait disturbance
    JP2003160480A (en) NK1 receptor antagonist

    Legal Events

    Date Code Title Description
    PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

    Free format text: ORIGINAL CODE: 0009012

    17P Request for examination filed

    Effective date: 20040324

    AK Designated contracting states

    Kind code of ref document: A1

    Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR IE IT LI LU MC NL PT SE SK TR

    AX Request for extension of the european patent

    Extension state: AL LT LV MK RO SI

    RAP1 Party data changed (applicant data changed or rights of an application transferred)

    Owner name: EISAI R&D MANAGEMENT CO., LTD.

    A4 Supplementary search report drawn up and despatched

    Effective date: 20071112

    STAA Information on the status of an ep patent application or granted ep patent

    Free format text: STATUS: THE APPLICATION HAS BEEN WITHDRAWN

    18W Application withdrawn

    Effective date: 20090209